Method and an apparatus for generating shockwave, a method and an apparatus for accelerating particles, an apparatus for delivering drugs, and a method and an apparatus for delivering DNA

ABSTRACT

Shockwave is generated by applying a short pulse energy to a surface of a metal foil to be absorbed and cause vaporization and plasmatization of the metal foil, generating thereby a jet by a sudden expansion of metal gas and thereby generating a shockwave on a surface of an opposite side of the metal foil.

[0001] The present invention relates to a method and an apparatus for generating shockwave, a method for accelerating particles, a particle accelerating apparatus, a drug delivery apparatus, and/or a method and an apparatus for delivering DNA.

[0002] As molecular biology have recently explicated the cause of many diseases, the importance of gene therapy will expectedly still increase. The actual condition of arteriosclerosis is the inflammatory, hyperplastic reaction of the endothelium and/or smooth muscle of vessels against damage, and is considered to be a good application for the gene therapy. However, the delivery of DNA into cells requires virus vector, ribosome and others. With the usage of these means, infection and potential carcinogenesis are the serious risk factors for the application of gene therapy. Also, low efficiency of the DNA delivery is an obstacle.

[0003] For instance, stable gene growth can be achieved with retrovirus, but efficiency of the DNA is low and risk of corcinogenesis cannot be avoided. Adenovirus delivers DNA at higher efficiency rate, but immunoreaction and crytotoxicity is reportedly induced with this means, and the risk of delivering extraneous DNA to unintended organs has been pointed out. DNA delivery without using virus, on the other hand, may have less risk of toxicity but, due to the low efficiency and low growth level, this method has not been prevailing. Therefore, a method to deliver DNA physically and precisely to the limited target tissue or organ in situ may well decrease the difficulties to a large extent.

[0004] The particle delivery system (PDS) with the use of shockwave is a method to deliver DNA into cells which is attached to particles of gold or tungsten which is harmless to cells, which is then accelerated to the higher speed than sound by shockwave to pierce through cell membrane, thus delivered into cells. Investigations both in vitro and in vivo have proved that the DNA growth is sustained for a long period of time. Thus the PDS is considered to serve most suitably as a means of gene therapy.

[0005] Conventionally, the mainstream of the PDS has been such that burst of the compressed helium or nitrogen generates shockwave, and metallic micro particles are accelerated by the high speed airflow behind the shockwave.

[0006] However, when the conventional PDS is redirected and applied from intravitam, especially intravascular therapy, to gene therapy, problems will arise such as troublesome handling of compressed gas and the hampering large size of the apparatus console.

[0007] The present invention is directed to remedy these problems with the conventional PDS wherein the purpose is to provide a new method for generating shockwave which allows miniaturization, better maneuverability and higher reliability and an apparatus thereby, a method for accelerating particles and an apparatus thereby, an apparatus for delivering drugs, a method for delivering DNA and an apparatus thereby.

[0008] The inventor et al of the present invention has developed a totally new DNA delivery apparatus by means of laser ablation and researched primarily on the possibility of gene therapy using the apparatus to treat obstructive cerebrovascular disease.

[0009] It is a feature of the present invention that, in order to achieve the above mentioned purpose, the method for generating shockwave is such that a short pulse energy, which is absorbed and causes vaporization and plasmatization of the metal, is applied on a surface of the metal foil, thus jet is generated by a sudden expansion of the metal gas and wherein shockwave is generated on the surface of the other side of the said metal foil.

[0010] It is a feature of the present invention that the shockwave generating apparatus is comprised of a metal foil and an energy source which discharges short pulse energy which is applied on a side of the metal foil, thus absorbed and causes vaporization and plasmatization of the metal.

[0011] The said short pulse energy of the shockwave generating apparatus according to the present invention is preferably light energy including but not limited to laser light energy or electrical energy which induces electric discharge between the energy source and the said metal foil.

[0012] The said energy source of the shockwave generating apparatus according to the present invention can preferably adjust one or more elements such as pulse width, strength waveform, the amount of energy, and energy density of the said short pulse energy.

[0013] The thickness of the said metal foil according to the present invention is preferably unequal.

[0014] The method for generating shockwave and/or the shockwave generating apparatus according to the present invention has a capability to adjust characteristic of the shockwave to generate by changing the thickness of the metal used and/or the material of the metal used.

[0015] It is a feature of the present invention that the method for accelerating particles is such that a short pulse energy, which is absorbed and causes vaporization and plasmatization of the metal, is applied on the surface of the side of the metal foil, thus jet is generated by a sudden expansion of the metal gas and thus shockwave is generated on the surface of the other side of the said metal foil, which then accelerates the micro particles located on the said surface of the other side of the metal foil.

[0016] The method for accelerating particles according to the present invention is such that the said micro particles are comprised, for example, of inorganic substances including but not limited to metal, sapphire, diamond, alumina, and garnet.

[0017] With the method for accelerating particles according to the present invention, the said micro particles may be comprised of solid drugs.

[0018] It is a feature of the present invention that the apparatus for accelerating particles is such that is comprised of the said shockwave generating apparatus and a designated area for the micro particles to accelerate on the surface of the other side of the metal foil where the said short pulse energy is applied.

[0019] It is a feature of the present invention that the apparatus for delivering drugs is such that is comprised of the said shockwave generating apparatus and a designated area for the micro particles of solid drugs to deliver into organism on the surface of the other side of the metal foil where the said short pulse energy is applied.

[0020] It is a feature of the present invention that the method for delivering DNA is such that a short pulse energy, which is absorbed and causes vaporization and plasmatization of a metal, is applied on the surface of a side of the metal foil, thus jet is generated by a sudden expansion of the metal gas and thus shockwave is generated on the surface of the other side of the said metal foil, which then accelerates the micro particles carrying DNA located on the said surface of the other side of the metal foil to deliver DNA into organism cells.

[0021] The method for delivering DNA according to the present invention preferably deliver the said micro particles carrying DNA into human body cells adjusting the depth of its travel.

[0022] It is a feature of the present invention that the apparatus for delivering DNA is such that is comprised of the said shockwave generating apparatus and a designated area for the micro particles carrying DNA on the surface of the other side of the metal foil where the said short pulse energy is applied.

[0023] According to the present invention, short pulse energy such as Q-switch laser light irradiated to a metal foil induces dissolution and, as a result of its reaction, shockwave is generated in the metal foil. The shockwave is reflected on the surface of the other side of the metal foil as expanded wave, thus the metal foil is deformed instantaneously and the micro particle on the metal foil is blasted off at an extremely high speed. This principle is simple so that the method is applied to almost all the area of human body with the use of endoscopes, thus flexible and variable introduction of gene therapy can be achieved.

[0024] The form of applying the present invention is described in conjunction with the accompanying drawings.

[0025]FIGS. 1 through 3 are illustrative views of the form of applying the present invention.

[0026] As FIGS. 1 and 2 illustrate, the shockwave generating apparatus is comprised of the electrical power source 1 for the laser, a Q-switch laser system 2, a refractive mirror 3, a lens 4, a metal foil 5, and a screen 6.

[0027] The shockwave generating apparatus operates in such a way that the electrical power source 1 ignites the Q-switch laser system 2 to generate a laser beam 7, which is then reflected by a refractive mirror 3 and focused by a lens 4 to irradiate on the surface 5 a of a side of a metal foil 5. The generated laser beam 7 is the short pulse energy which is absorbed and causes vaporization and plasmatization of the metal foil 5. The DNA delivery apparatus is comprised of the designated area for the micro particles 9 which carry DNA 8 on the surface 5 b of the opposite side of the surface 5 a where the laser beam 7 is irradiated. The metal foil 5 is placed so that the surface 5 b faces toward an organism A which DNA 8 is aimed at.

[0028] The DNA delivery apparatus is formed as illustrated in FIG. 3 (A) so that the Q-switch laser beam 7 is irradiated to the metal foil 5 of 001 to 0.1 mm thick to form the spot of 2 to 3 mm in diameter with an even intensity distribution. The irradiation as illustrated in FIG. 3 (B) generates jet due to the instantaneous expansion of the metal gas, thus plane shockwave 11 is easily created in the metal at a speed of 5 km/s with a diameter of 2 to 3 mm.

[0029] Separately and previously, the metal micro particles 9 of 1 micron in diameter which have been coated with DNA 8 are placed on the surface 5 b of the opposite side of the surface 5 a of the side of the metal foil 5 which the laser beam targets. As the shockwave reflects on the surface 5 b on the opposite side of the metal foil 5 and turns into reflected wave 12, extremely high acceleration is generated on the surface 5 b, which then accelerates the metal micro particle 9 on the surface 5 b. As a result, as illustrated in FIG. 3 (C), the metal micro particle 9 makes free flight toward and through cells of organism A in order to physically deliver extraneous DNA 8 into the target cells.

[0030] In order to control the flight of the micro particle 9 or micro carrier, a screen 6 has previously been placed at a certain distance, 0.5 to 1.0 mm for instance, from the organism A. The relationship between the power of laser beam and the flight speed and the penetration depth is verified experimentally and numeric-analytically. When the apparatus is applied in vivo, a layer of carbon dioxide gas 13 is placed to secure free flight space between the organism A and the metal foil 5 or the screen 6.

[0031] According to the DNA delivery apparatus, miniaturization of the apparatus can be realized to operate in conjunction with endoscopes of 2 mm or smaller in diameter. Thus, convenient and selective gene therapy for a narrow surgical site is achieved; prevention of post angioplasty restenosis is available and/or bloodstream can be revived at a slow pace in order to avoid hyperperfusion syndrome due to abrupt revival of bloodstream. In these cases, delivery of DNA intravascularly to the target area in a safe and precise manner can be achieved. Combination of method for DNA delivery by shockwave and intravascular technique can overcome various difficulties concerning DNA delivery to organism. The said DNA delivery apparatus enables miniaturization of the apparatus comparatively with ease. It further enables control voluntarily over the direction of carrier particle to an extent.

[0032] The method for delivering DNA and the DNA delivery apparatus can be applied to prevent restenosis after percutaneous angioplasty for obstructive cerebrovascular disease, or to revive bloodstream at a slow pace in order to avoid hyperperfusion syndrome due to abrupt revival of bloodstream. The method for delivering DNA and the DNA delivery apparatus further can be applied to many other diseases by changing DNA to deliver. For example, during brain tumor enucleation, DNA delivery can easily be conducted as a combination therapy to the surface of the cavity after the enucleation for the remaining tumor. Furthermore, in conjunction with endoscopes, gene therapy becomes available for tumors in oral cavity or on the surface of bronchial tubes, or tumors in digestive tract.

[0033] Furthermore, micro particles of solid drugs can be accelerated and delivered to organism in place of micro particle coated with DNA 8. Thus, it can be utilized not only as gene therapy for tumors but also as the method for delivering drug(s) or a drug delivery apparatus without an injection needle. The method for delivering DNA and the DNA delivery apparatus according to the form of applying the present invention can contribute to modern medicine and surgery tremendously. Especially research on gene therapy for obstructive cerebrovascular disease has yet rarely been reported both nationally and internationally. In the circumstances where the aging society is prevailing and cerebral apoplexy has been increasing, to establish a clinical application of the method is an urgent matter.

[0034] As illustrated in FIG. 2, a DNA delivery apparatus is operated and Q-switch Glass laser beam (wavelength 1.06 microns, pulse width 7 nsec, pulse energy 3.6 J) was irradiated with the spot of 2.0 mm in diameter to an aluminum foil. On the surface 5 b on the opposite side of the surface 5 a which the laser beam was irradiated, Si micro particles 9 of 20 microns, in diameter are pasted. The result of the laser irradiation is that the shockwave was generated in the aluminum foil, thus the Si micro particles 9 were accelerated at the speed of 100 to 500 m/sec and blasted off from the aluminum foil.

[0035] The present invention can provide miniaturization, maneuverability and reliability to a method and an apparatus for generating shockwave, a method and an apparatus for accelerating particles, an apparatus for delivering drugs, and a method and an apparatus for delivering DNA. 

1. A method for generating shockwave wherein a short pulse energy, which is absorbed and causes vaporization and plasmatization of the metal, is applied on a surface of a metal foil, thus jet is generated by a sudden expansion of metal gas and wherein shockwave is generated on the surface of the other side of the metal foil.
 2. An apparatus for generating shockwave comprised of a metal foil and an energy source to discharge short pulse energy which is applied on a surface of the metal foil, thus absorbed and causes vaporization and plasmatization of the metal.
 3. An apparatus for generating shockwave as claimed in claim 2 wherein the said short pulse energy is light energy including but not limited to laser light energy or electrical energy which induces electric discharge between the energy source and the said metal foil.
 4. An apparatus for generating shockwave as claimed in claim 2 or 3 wherein the said energy source can adjust one or more elements such as pulse width, strength waveform, amount of energy, and energy density of the said short pulse energy.
 5. An apparatus for generating shockwave as claimed in claim 2 or 3 wherein the thickness of the said metal foil is unequal.
 6. A method for accelerating particles wherein a short pulse energy, which is absorbed and causes vaporization and plasmatization of the metal, is applied on a surface of the metal foil, thus jet is generated by a sudden expansion of the metal gas and wherein shockwave is generated on the surface of the other side of the said metal foil, which then accelerates micro particles located on the said surface of the other side of the metal foil.
 7. A method for accelerating particles as claimed in claim 6 wherein the said micro particles are comprised of inorganic substances including but not limited to metal, sapphire, diamond, alumina, and garnet.
 8. A method for accelerating particles as claimed in claim 6 wherein the said micro particles are comprised of solid drugs.
 9. An apparatus for accelerating particles comprised of an apparatus for generating shockwave as claimed in claim 2 or 3 and a designated area for the micro particles to accelerate on the surface of the opposite side of the surface where the said short pulse energy is applied.
 10. An apparatus for delivering drugs comprised of an apparatus for generating shockwave as claimed in claim 2 or 3 and a designated area for the micro particles of solid drugs to deliver into an organism on the surface of the opposite side of the surface where the said short pulse energy is applied.
 11. A method for delivering DNA wherein a short pulse energy, which is absorbed and causes vaporization and plasmatization of a metal, is applied on a surface of the metal foil, thus jet is generated by a sudden expansion of the metal gas and wherein shockwave is generated on the surface of the opposite side of the said metal foil, which then accelerates the micro particles carrying DNA located on the said surface of the opposite side of the metal foil to deliver DNA into the organism cells.
 12. A method delivering DNA as claimed in claim 11 wherein the said micro particles carrying DNA is delivered into the organism cells with a capability of adjusting the depth of its travel.
 13. An apparatus for delivering DNA comprised of an apparatus for generating shockwave as claimed in claim 2 or 3 and an designated area for the micro particles carrying DNA on the surface of the opposite side of the surface where the said short pulse energy is applied. 